Hydroxy substituted triphenyl vinyl halides



Patented Oct. 21, 1947 UNITED STATES PATENT QFFI-CE VINYLHAL IDES Chafis F. Longfellow, moomfieiaand 515mm. o; Jackson, Nutley, N. J assrg-nors tog; w flarrrrick Company, Newark, N. J a corporation of New Jersey No Drawing. Application pril 29 1944-, Serial No. 533,394

6 Clairiis. (o1. zed-tie) This invention relates to compounds having estrogenio acti ity and more particularly to certaifyhydrojzy sulistitutd triph'nyl vinyl'halides having this property;

. v .4 fi jfimr'e' Q'th n -i h e also been proposed as havin estroge'riic ac: -i W 1" In accordanoei with our invention, we'have discovered that commu owwow are quite differ; ent' in chemical structurefrom these compounds n'rehtioned; nevertheless pfossess' marked estro genie activity. These cornpoun'ds also have other l' 'b T i IQ sul'i ii i' lm i i fu f 5 reactions and" other ch acteristicswhich'render then; A tra t-1e ror adm nistration In addition they maybe synthesized by a -process which can be ead ly practiced on a' commercial scale. 4 1 4 new are ,d'fiq i Y n s w re l fo oeeeic empt s ihe' t pe d scribed more particularly herei other objects will appear from the following description.

The compoundscomprisedinour invention may be regarded as hydroxy triphenyl vinyl halides and may be" viewed as haw'ng -the general formula R iii i t Xi a fi l 'fizm9rm i i ular y c ic-- rine or bromine, andirr Which-R is H or OH, and i Q QL, v V

The compounds may beforgned byaprocess in i h an a Qr e rd re nt i m t w h a pl o eem lex d ar'r 'orhr x d l kewere with the subsequent decomposition of the addition product to form the corresponding carbinolorethylene; The carbinol or ethylene may 9hel eene ed. .d re tly to. m the cqrr p n ing triphenyl vinyl halide having at least one Chemical s truc tiireto" hydroxy group, substitutedinat least one of the three phenyl groups.

The reaction may be illustrated by the following general formulae:

where X, and R are the same as has been defined previously. e

In order to describe piore particularly the compounds comprised in the invention, and the methods by which they may be prepared, the following examples are given'merely as illustrative and without any limitationgn the scope of the invention as defined heretofore? T0321) gfiofgmagriesiuni is added 250cc; of dry ether anda crystaliof iodinel Into this mrx turei is'introdu'ced 16815 g. .o'f.benz'y1 chloride in 550. cc. of dry ether at sueh'aiirate as to keep the I ether, refluxing. After all ofthe benzylchlorid has; been added; 6610 g"; .of p-hydr'oxybnzophe nOh-adissolived- 1000 ccLof dry ether, is added; dropwise whileex'terndlihetut is applied to keep the ether refluxing. After all'ofjthe keton'e is:

added, the; reaction 'mixtu'r'e is'refiuxed for about another hour. p

After the' reactionniixture has cooled to room temperature, 700 g. of 'icefand 200cc; of water chloride and g. of bromine in 100 cc. of carbon tetrachloride is added dropwise. A slight rise in the temperature of the solution results and copious quantities of hydrogen bromide are eliminated. After all of the bromine has been added the solution is concentrated to one half volume and cooled. The solution fills with a solid which is recrystallized from xylene. The product formed is 12'diphenyl'z'p-hydroxyphenyl Vmyl: 'droXy phenyl-2-phenyl vinyl chlorides may be bromide, which melts initially at 147-9 Several made by modifying the process as indicated in recrystallizations from methyl alcohol yields a product melting at 158-60. This compound has the following formula:

Example 2 To 29.0 g. of 1,2-diphenyl-l-p-hydroxyphenyl ethanol, which is the inter-mediate carbinol prepared in accordance with'Example'l, dissolved in 150 cc. of acetic acid is added 7.1 gms. of chlorine. From this reaction mixture after the removal of the acetic acid, there is obtained, by crystallization from a 50-50 mixture of petroleum ether and carbon tetrachloride, a1,2diphenyl-2-p-hydroxyphenyl Vinyl chloride melting at 101-3".

Recrystallization of this'u-LZ-diphenyI-Z-phydroxyphenyl vinyl chloride from 75% methyl alcohol finally yields the ,3 form of the same compound melting at 136-8". These two compounds are believed to be stereo isomers and have the following formula:

' Example 3- The Grignard reagent fromr9.5 g. of magnesium and 64 g. of p-chlorobenzyl' chloride is made by the usual procedure. To this reagent in 350 cc. of dry ether, is added 20 g. of p-hydroxybenzophenone in 350 cc; of dry ether while the solution is refluxed by application of external heat for three hours. To. this ether solution, after cooling, is added 300 g. of ice, 100 cc. of water and 100 g. of ammonium chloride. The ether layer is separated and washed with water. The ether is removed by distillation and xylene is added to the residue. Cooling the xylene solution yields a product melting at 1346. Recrystallization from xylene yields l-p-hydroxyphenyl-l-phenyl- Z-p-chlorophenyl ethylene melting at 139-140".

To 10 g. of the above intermediate ethylene, in 350 cc. of carbon tetrachloride, is added dropwise 4.6 g. of bromine in 50 cc. of carbon tetrachloride. After all the bromine has been added, the solution is concentrated to 50 cc. and cooled. The solid is filtered and recrystallized from a 50-50 mixture of petroleum ether and carbon tetrachloride to yield a product melting at 130-5". Recrystallization of this product from xylene yield l-p-chlorophenyl 2 p-hydroxyphenyl-2- phenyl vinyl bromide melting at 141-3". This product has a composition indicated by the following formula:

The corresponding 1-p-chlorophenyl-2-p-hy- Example 2.

Example 4 The Grignard reagent from 85.5 g. of benzyl chloride and 18.0 g. of magnesium isprepared in the usual manner. To this reagent in 500 cc. of dry ether is added dropwise 18.0 g. 4,4'-dihydroxybenzophenone in 1600 cc. of ether. Throughout the addition of the 'ketone, the ether is kept refluxing by external heat. Total heating period is 13 hours. To the cool solution is added 500 g. of'ice, 500 cc. of Water and g. of ammonium chloride. The ether solution is separated and washed with water. The ether is distilled. The residue is cooled in the ice box. Some unreacted ketone is removed. The mother liquor is concentrated and the residue recrystallized from benzene. to, yield 1,1-di-(p-hydroxyphenyl)-2- phenyl ethylene melting at 179-81.

To 3.0 g. of the above intermediate ethylene, in 50 cc. of acetic acid, is added dropwise 1.6 g. brorninev in 10 cc. of acetic acid. The reactants are poured onto ice. The solid is filtered and washed with water. The product is recrystallized from benzene to yield 1-phenyl-2,2-di-(p-hydroxyphenyl), vinyl bromide melting with decomposition at '209-l0. This compound is'believed to have a formula as follows;

The 1-phenyl-2,2-di-(p-hydroxyphenyl) vinyl chloride may be made by modifying the process as indicated in Example 2, and the l-p-chlorophenyl-2,2-di-(p-hydroxyphenyl) vinyl bromide and chloride may be made by modifying the process as indicated in Example 3. p

In the above examples the temperatures are givenin degrees centigrade.

All of the above compounds have been made, their structure established, a'nd their estrogenic activity has been demonstrated by biological tests. Many compounds similar to them have been made and have been found not to have estrogenic activity. From a widevarie'ty of such compounds studied it has been established that the presence of the hydroxy group is essential to the desired estrogenic activity.

One skilled in the art, in view of the illustrative examples, and the general method of making them, will be enabled to prepare many other compounds falling within the novel type of estrogenic compounds comprising our invention, as set forth in the following claims.

We claim:

1. Estrogenic compounds having the follow-- ing general formula:

where X is selected from the group consisting of bromine and chlorine, R. is selected from the group consisting of H and OH, and R is selected from the group consisting of H and. Cl.

Estrogenic compounds having the following formula:

where X is selected from the group consisting of bromine and chlorine.

3. Estrogenic compounds having the following formula:

where X is selected from the group consisting of bromine and chlorine.

4. An estrogenic compound of the following .formula:

10 5. Estrogenic compounds having the following eneral formula:

6. An estrogenic compound of the formula:

C. F. LONGFELLOW.

ARNOLD O. JACKSON.

Robson et al., Nature, vol. 150, pp. 22-23, July 4, 1942.

Koelsch, J our. Am. Chem. Soc. vol. 54, p. 2487-2493 (1932).

Dodds et al., Nature, vol. 142, p. 212, July 30, 1938.

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